1. Field of the Invention
This invention concerns a method and agents for control, management and inhibition of a preterm labor or for inducing labor in overterm pregnancy by providing to a pregnant woman or pregnant mammal a donor or inhibitor of nitric oxide alone or in combination with other enhancing or modulating agents. In particular, this invention concerns a method for management and inhibition of preterm labor by administering to a pregnant woman a nitric oxide source in a safe and non-toxic concentration during the preterm labor or a nitric oxide inhibitor during the overterm pregnancy.
2. Background and Related Disclosures
Spontaneous preterm labor during pregnancy remains an enormous, and apparently increasing problem confronting the medical community. Only few advances have been made in the understanding of causes of preterm labor, in the early detection of preterm labor and in its general management. Major advances so far have occurred in fetal and neonatal care ameliorating or preventing pathophysiological consequences to the prematurely born infant. However the ability to definitely and safely stop preterm labor and thereby to allow a pregnancy to advance towards term has thus far eluded the medical and scientific community.
In humans, the maintenance of pregnancy as well as onset of labor appears to depend on multiple factors. Normal progression of pregnancy until the term requires relaxation of uterine smooth muscle until parturition, but the mechanism that maintains uterine relaxation during pregnancy is unknown. Normal parturition typically begins with labor. Labor consists of a series of rhythmic, progressive contractions of the uterus that cause effacement and dilation of the uterine cervix. In normal pregnancy, labor usually begins within two weeks before estimated delivery.
Diagnosis of spontaneous preterm labor is made upon the onset of labor when regular uterine contraction are accompanied by progressive cervical dilation and/or effacement before 37 week of gestation. If the preterm labor is let to continue unhindered it results in preterm delivery. Preterm delivery accounts for a major proportion of perinatal deaths and significant proportion of postnatal and childhood defects and therefore, maintaining the fetus in utero is preferred to allowing preterm delivery.
Preterm labor, whether occurring spontaneously or the one which invariably follows any significant transuterine fetal manipulation from needle puncture to fetoscopy to hysterotomy for fetal surgery, presents a serious problem and in later case has proven to be a limiting factor for all types of fetal intervention. The very severe form of spontaneous preterm labor or labor induced by an incision in the gravid uterus for open fetal surgery is resistant to all known forms of tocolysis attempted both experimentally and clinically over the last decade. Indeed the management of preterm labor after fetal surgery is particularly difficult and dangerous for mother and fetus because aggressive treatment with magnesium sulfate, betamimetics and other hemodynamically-active tocolytic agents has resulted in sequelae for both mother and fetus.
Once preterm labor is diagnosed, the risks and benefits of labor inhibition must be weighed against those of allowing delivery to occur. The risks from labor inhibition are primarily related to the side effects of the labor inhibiting drugs. Once preterm labor is diagnosed and the gestational age is established as appropriate for labor inhibition, contraindications such as eclampsia, preeclampsia, ruptured placenta, dead or anomalous fetus, fetal distress or chorioammionitis to premature delivery is determined and the particular available tocolytic agent is selected. Until now, tocolytic agents most often used to inhibit preterm labor are .beta.-adrenoreceptor stimulants such as epinephrine or its synthetic analogs and derivatives salbutamol, terbutaline, isoxsuprine, ritodrine, and fenoterol, magnesium sulfate, prostaglandin inhibitors such as aspirin indomethacin and naproxen, ethanol and calcium channel-blocking agents such as nipedifine or nicardipine. However, the potential adverse effects of these drugs limit their use.
Patients undergoing hysterotomy and fetal surgery typically experience difficulty with preterm labor despite treatment involving a regimen of preoperative indomethacin, intraoperative deep halogenated inhalation anesthesia, and postoperative indocin, magnesium sulfate, and betamimetics. The majority of these patients has visible and palpable intraoperative uterine contractions often associated with fetal bradycardia from cord compression. These intraoperative contractions respond erratically to deepening anesthesia and to acute administration of magnesium sulfate or terbutaline. All the patients have significant labor postoperatively which in mild form can be controlled by intravenous tocolytics administered during several days, but in severe form can take a week or longer to control with intravenous medication before they could be weaned to oral or subcutaneous pump medication. All patients undergoing hysterotomy eventually develop uncontrolled preterm labor, premature rupture of membranes, and premature delivery from 27-34 weeks gestation.
It is clear that even the best tocolytic regimen available currently is unsatisfactory for prevention or inhibition of preterm labor. Additionally to proving ineffective, such standard tocolytic regimen had potentially serious harmful effects on both mother and fetus. Halogenated inhalation anesthesia needed to achieve uterine relaxation had been shown to produce significant myocardial depression in both mother and fetus, the indomethacin produces constriction of the fetal ductus arteriosus, and serial echocardiograms in patients demonstrated that ductal constriction producing tricuspid regurgitation can lead to significant right-heart failure in the fetus. Perhaps even more important, indomethacin tocolysis has recently been shown to be associated with an increased risk of perinatal intracranial hemorrhage in the neonate. Finally, it is becoming obvious that the aggressive treatment of postoperative labor with maximal doses of magnesium and betamimetics is quite toxic for the mother and attempts to avoid maternal pulmonary edema in this clinical setting led to maternal hypovolemia with documented reversal of diastolic flow in the uterine arteries. It, therefore, appears that currently available tocolytic treatment has significant potential to harm the fetus.
Different pharmacological approaches using the above tocolytic drugs have been tried to control preterm labor, but even ritodrine which has been specifically synthesized for use in obstetrics and gained wide general acceptance and application, has now come under significant scrutiny and its effectivity and safety is being questioned. A major underlying cause for this lack of effective treatment of preterm labor is insufficient information on the basic physiology of uterine smooth muscle and therefore the inability to formulate therapeutic strategies based on a true understanding of the mechanisms involved.
The study of preterm labor and discovery of new approaches toward prevention, management and treatment of preterm labor is therefore extremely desirable.
Nitric oxide (NO) is a free radical with a very short half-life. Nitric oxide is synthesized from the amino acid L-arginine by the nitric oxide synthase (NOS). So far, the only clearly established role for nitric oxide is as a cytotoxic molecule for invading microorganisms and tumor cells. However, other physiological activity, such as acting as a neurotransmitter in the brain and in the periphery, affecting GI tract motility and penile erection were also observed. Nitric oxide is produced in vascular endothelial cells by the nitric oxide synthase and seems to mediate vascular smooth muscle relaxation by increasing levels of cGMP. Its effect on relaxation of intrapulmonary artery and vein was described in J. Pharmacol. Exp. Ther., 228:33-42 (1984).
Nitric oxide, its physiology, pathophysiology and pharmacology is described in Pharmacological Reviews, 43:109-134 (1991). While there were some in vitro studies described in Brit. J. Pharmacol., 34:604-612 (1968) concerning the effect of nitric oxide precursors on animal isolated uterus, such studies did not lead to any conclusion or advancement useful for control of labor, particularly preterm labor in human or mammal pregnancy.
It would be therefore highly advantageous to provide a method and agents which would, in a rational and reproducible way, control, manage and inhibit preterm labor or, when applicable, induce labor in late pregnancies when such induction of labor is indicated.
The current invention provides a method and agents which enable clinicians to control, manipulate or inhibit preterm labor or induce labor in late pregnancies in safe and reproducible way. The method gives a clinician control over the labor progression until now unavailable, by administering to a pregnant woman nitric oxide source or inhibitors, alone or in a suitable combination with other agents and with pharmaceutically acceptable excipients. Such treatment has not been heretofore available.
All patents and publications cited herein are hereby incorporated by reference in their entirety.